This proposal titled "Combination Growth Factor Antagonist/Chemotherapy in PCa" is a request for a NCI Mentored Patient-Oriented Research Career Development Award (K23). The candidate is interested in the study of growth factor receptor tyrosine kinases (RTKs) and their relevance in prostate cancer. There is emerging evidence that certain RTKs, specifically platelet derived growth factor receptor (PDGFr) and epidermal growth factor receptor (EGFr) have a role in the growth advanced hormone independent prostate cancer. Small molecules which inhibit the phosphorylation of these receptors appear to have a cytostatic effect on neoplastic cell growth including in prostate cancer cells. The candidate is currently enrolled in a formal clinical investigation training program designed to educate investigators in early drug development. The proposed project is designed to test the hypothesis that combination therapy with PDGFr or EGFr antagonists with cytotoxic chemotherapy can be synergistic in the treatment of advanced prostate cancer. This proposal will provide experience in developing a therapeutic approach in the preclinical model and translating these findings into a clinical trial to evaluate their role in the treatment of human prostate cancer. The first phase will determine the in vivo molecular interaction of these agents with DNA damaging chemotherapy. These will then be tested in prostate cancer xenografts and in the orthotopic model. The third phase will evaluate the optimal combinations in human clinical trials with pharmacodynamic endpoints. This research project is designed to integrate the preclinical investigation of these novel agents with effective clinical evaluation in order to optimize their development. This will guide the development of the candidate into an independent translational investigator in prostate cancer. The research conducted will expand the current knowledge of the biology of hormone independent prostate cancer and its management.